Nearly 12 million adults in the United States have been diagnosed with chronic obstructive pulmonary disease, with roughly 180,000 patients dying annually with end-stage refractory lung diseases. The only option currently available is lung transplantation, with high mortality rates due to the lack of donor organs. Current research is investing much time and resources into bioengineering strategies to regenerate lungs, however, to-date it has not been possible to replicate fully functioning, viable lungs for transplantation. Now, a study from researchers at Columbia University grows fully operational lungs in mouse embryos using transplanted stem cells. The team states their novel technique takes a step closer to growing human lungs in animals for patients who need transplants and to study new lung treatments. The study is published in the journal Nature Medicine.
Previous studies report major efforts to bioengineer lungs by growing stem cells on synthetic scaffolds or in ‘ghost’ lungs stripped of their original cells. Though much progress has been made, researchers are yet to generate a viable lung capable of maintaining survival in animal models, or capable of keeping an animal alive. This is because modeling the structural and functional complexities of the lung in vitro has been made impossible given its complex 3-dimensional structure and cellular diversity exacting precise alignment. The current study grows new lungs from foreign stem cells in a developing animal to take advantage of the animal’s natural signals for lung organogenesis before birth.
The current study creates tissue culture conditions, known as conditional blastocyst complementation, allowing donor mouse pluripotent stem cells to proliferate and maintain their ability to transform into different cell types. The donor mouse pluripotent stem cells were implanted in two types of engineered mouse embryos, one of which lacked the stem cells to develop into mature lung cells, and another which cannot produce enough of the cells to make a lung. Results show this procedure successfully engineered a ‘chimeric’ embryo that is a mix of donor and host cells.
Data findings show the implanted stem cells outcompeted the host cells for growth-promoting molecules present in the embryo, leading to the formation of working lungs enabling the mice to live well into adulthood. The group states a variety of lung function tests confirmed the donor cell lungs worked as well as normal mouse lungs, with no signs of rejection. They go on to explain the stem cells were implanted before the embryos’ immunological system was turned on, which may explain why the organs were not rejected.
The team surmises they have successfully generated functional chimeric lungs in mice unable to develop lungs, using donor mouse pluripotent stem cells. For the future, the researchers state their work paves the way for the generation of lungs in large animals for transplantation to humans.
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